Demyelinating and dysmyelinating disorders include a large number of degenerative conditions in humans including Multiple Sclerosis. Recently, myelin involvement in psychiatric disorders such as schizophrenia was also suggested. Understanding how myelin is synthesized and properly maintained is a challenging task that has been under intense investigation for decades. However, our knowledge of these processes is still limited and effective treatments for most of the demyelinating/dysmyelinating diseases are absent. Adult-onset autosomal dominant leukodystrophy (ADLD) is a slowly progressive, neurological disorder characterized by symmetrical widespread myelin loss in the CNS, with a phenotype similar to chronic progressive multiple sclerosis (MS). We have recently identified a genomic duplication that causes ADLD. Patients carry an extra copy of the gene for the nuclear lamina protein, Lamin B1, resulting in increased gene dosage in ADLD brain tissue. Increased expression of Lamin B1 in Drosophila resulted in a degenerative phenotype. In addition, an abnormal nuclear morphology was apparent when cultured cells over-expressed this protein. This is the first human disease attributable to Lamin B1 mutations. Antibodies to Lamin B are found in autoimmune diseases and it is also an antigen recognized by a monoclonal antibody, J1-31, raised against plaques dissected from MS patient brains. This raises the possibility that it may be linked to the autoimmune attack that occurs in MS. In this grant, we propose to study the expression pattern and regulation of Lamin B1 to lay a foundation for future investigation into the mechanism by which Lamin B1 regulates proper myelin maintenance. We have generated BAC and cDNA transgenic mouse models that express less than four extra copies of LMNB1 genes. We are also in the process of generating conditional (under tet regulation) overexpression mouse models. Characterization of these mice will provide insight into the mechanisms not only for ADLD pathophysiology but also for myelin biogenesis. In addition, we identified miR-23 as a negative regulator of Lamin B1. We propose to use primary culture and co-culture methods to study the effect of Lamin B1 and miR-23 in oligodendrocyte development and myelination. Such knowledge will yield insights into pathways through which Lamin B1 overexpression leads to demyelination. Understanding the mechanism of this demyelinating disorder may provide clues to pathways that modulate the expression of acquired leukodystrophies. Ultimately, this knowledge will provide new insight in the synthesis and maintenance of myelin and identify novel targets for developing therapeutic interventions for stimulating remyelination in common disorders like MS.